Stabilization of speckle-type POZ protein (Spop) by daz interacting protein 1 (Dzip1) is essential for gli turnover and the proper output of hedgehog signaling

Tyler Schwend, Zhigang Jin, Kai Jiang, Brian J. Mitchell, Jianhang Jia, Jing Yang*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

The Hedgehog (Hh) pathway is essential for embryonic development and adult tissue homeostasis. The Gli/Cubitus interruptus (Ci) family of transcription factors acts at the downstream end of the pathway to mediate Hh signaling. Both Hh-dependent and -independent Gli regulatory mechanisms are important for the output of Hh signaling. Daz interacting protein 1 (Dzip1) has bipartite positive and negative functions in the Hh pathway. The positive Hh regulatory function appears to be attributed to a requirement for Dzip1 during ciliogenesis. The mechanism by which Dzip1 inhibits Hh signaling, however, remains largely unclear. We recently found that Dzip1 is required for Gli turnover, which may account for its inhibitory function in Hh signaling. Here, we report that Dzip1 regulates Gli/Ci turnover by preventing degradation of speckle-type POZ protein (Spop), a protein that promotes proteasome-dependent turnover of Gli proteins. We provide evidence that Dzip1 regulates the stability of Spop independent of its function in ciliogenesis. Partial knockdown of Dzip1 to levels insufficient for perturbing ciliogenesis, sensitized Xenopus embryos to Hh signaling, leading to phenotypes that resemble activation of Hh signaling. Importantly, overexpression of Spop was able to restore proper Gli protein turnover and rescue phenotypes in Dzip1-depleted embryos. Consistently, depletion of Dzip1 in Drosophila S2 cells destabilized Hh-inducedBTBprotein (HIB), the Drosophila homolog of Spop, and increased the level of Ci. Thus, Dzip1-dependent stabilization of Spop/HIB is evolutionarily conserved and essential for proper regulation of Gli/Ci proteins in the Hh pathway.

Original languageEnglish (US)
Pages (from-to)32809-32820
Number of pages12
JournalJournal of Biological Chemistry
Volume288
Issue number45
DOIs
StatePublished - Nov 8 2013

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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